PROJECT SUMMARY Antiretroviral therapy (ART) has dramatically improved the prognosis of people living with human immunodeficiency virus (HIV) infection. However, ART alone cannot eradicate the infection and therefore, daily treatment must be maintained for life to prevent relapse of uncontrolled viral replication and resumption of disease progression. Unfortunately, in addition to persistent stigma associated with HIV infection, lifelong treatment entails both health risks to treated individuals and a significant economic burden to society. As such, there is a desperate need to develop novel therapeutic interventions that can cure HIV infection. It is now well established that initiation of ART in the first days/weeks after infection does not prevent the establishment of a long-lived viral reservoir, although it is effective at reducing its size. Another strategy aimed at reducing the reservoir is to induce HIV gene expression in individuals on suppressive ART with the goal of eliminating latently infected cells, which could ultimately lead to virus eradication. However, purging the HIV reservoir not only requires the induction of viral replication by latency-reversing agents (LRA) but also the elimination of these reactivating latently-infected cells by either viral cytopathic effects or immune cell-mediated killing, so called ?shock and kill?. This killing is often inefficient when LRAs are administered to HIV-infected individuals after several years of ART, possibly due to low level antigen expression, negative impact of LRAs on clearance mechanisms or the low frequencies of effective HIV-specific CD8+ T cells. Here we propose to evaluate a novel strategy in which an LRA is administered together with ART during acute infection. We believe this ?window of opportunity? when the immune responses are still present and the latent reservoir is easier to reactivate will improve the efficacy of the ?shock and kill HIV? approach to a cure. To address this, we will use GSK445A, a stabilized Ingenol-B based Protein Kinase C agonist (PKC) that we have shown can induce HIV/SIV transcription in vitro and in vivo in SIV-infected rhesus macaques (RM) on ART without significant toxicity. We propose to further optimize our strategy by evaluating if combining GSK445A with IL-15 can enhance the therapeutic effect. As such, the goal of this R01 is to determine whether administering this potent LRA during acute SIV infection, at the time of ART initiation, will delay or prevent viral rebound after ART cessation. The demonstration of therapeutic efficacy in this project will provide strong impetus for assessment of this concept in recently infected HIV+ individuals.